6-amino-5-(3-bromocinnamoylamino)-3-propargyluracil | 199680-59-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: 6-amino-5-(3-bromocinnamoylamino)-3-propargyluracil
• 英文别名: (E)-N-(6-amino-2,4-dioxo-3-prop-2-ynyl-1H-pyrimidin-5-yl)-3-(3-bromophenyl)prop-2-enamide
• CAS: 199680-59-6
• 化学式: C₁₆H₁₃BrN₄O₃
• 分子量: 389.208
• InChiKey: GATZSBQJLGAIJO-VOTSOKGWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-amino-5-(3-bromocinnamoylamino)-3-propargyluracil 在 sodium hydroxide 、 potassium carbonate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 8-(m-bromostyryl)-3-(2-hydroxyethyl)-1-propargylxanthine
  参考文献：
  名称：

  Water-Soluble Phosphate Prodrugs of 1-Propargyl-8-styrylxanthine Derivatives, A_2A-Selective Adenosine Receptor Antagonists

  摘要：

  Water-soluble prodrugs of potent, A(2A)-selective adenosine receptor (AR) antagonists were prepared. 8-(m-Bromostyryl)-3,7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxystyryl)xanthine derivative (MS-DMPX, 5b) were used as starting points. It was found that polar functional groups suitable for the attachment of a prodrug moiety were tolerated on the styryl ring and even better on the 3-substituent. 8-(m-Hydroxystyryl)-DMPX (7) and 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-1-propargylxanthine (5e, MSX-2) were the most potent and A(2A)-selective compounds and were selected for prodrug formation. For the preparation of 5e a new ring-closure method was applied. Treatment of 6-amino-1-(3-hydroxypropyl)-5-(m-methoxycinnamoylamino) with hexamethyldisilazane at high temperature resulted in higher yields of the target xanthine than the standard ring-closure procedure using sodium hydroxide. Phosphate prodrugs were prepared by classical phosphorylation using phosphorus oxychloride and alternatively by using a phosphoramidite method. Phosphates of the aliphatic alcohol 5e could be obtained by both methods in similar yields. The phenolic compound 7, however, could be phosphorylated only by using the phosphoramidite method. The disodium salts of the phosphate prodrugs exhibited high water solubility (8-(m-methoxystyryl)-7-methyl-3-[3-O-phosphatylpropyl]-1-propargylxanthine disodium salt, 9b: 17 mM, 9 mg/mL). Prodrug 9b was found to be stable in aqueous solution (pH 7) but readily cleaved by phosphatases to liberate 5e (MSX-2). Compound 5e showed high affinity for rat A(2A) AR (K-i = 8 nM), human recombinant A(2A) AR (K-i = 5 nM), and human native A(2A) AR (K-i = 15 nM) and was highly selective versus rat A(1) AR (110-fold), human recombinant A(2A) AR (500-fold), human A(2B) AR (> 2000-fold), and human A(3) AR (>2000-fold).

  DOI：

  10.1021/jm9911480
• 作为产物：
  描述：

  3-溴肉桂酸 、 5,6-diamino-3-prop-2-ynyl-1H,3H-pyrimidine-2,4-dione 在 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 甲醇 为溶剂， 反应 24.0h， 以96%的产率得到6-amino-5-(3-bromocinnamoylamino)-3-propargyluracil
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 3,7-Dimethyl-1-propargylxanthine Derivatives, A_2A-Selective Adenosine Receptor Antagonists

  摘要：

  A series of 8-substituted derivatives of 3,7-dimethyl-1-propargylxanthine (DMPX) was synthesized and investigated as A(2A) adenosine receptor antagonists. Different synthetic strategies for the preparation of DMPX derivatives and analogues were explored. A recently developed synthetic procedure starting from 3-propargyl-5,6-diaminouracil proved to be the method of choice for the preparation of this type of xanthine derivatives. The novel compounds were investigated in radioligand binding studies at the high-affinity adenosine receptor subtypes A(1) and A(2A) and compared with standard A(2A) adenosine receptor antagonists. Structure-activity relationships were analyzed in detail. 8-Styryl-substituted DMPX derivatives were identified that exhibit high affinity and selectivity for A(2A) adenosine receptors, including 8-(m-chlorostyryl)-DMPX (CS-DMPX, K-i A(2A) = 13 nM, 100-fold selective), 8-(m-bromostyryl)-DMPX (BS-DMPX, K-i A(2A) = 8 nM, 146-fold selective), and 8-(3,4-dimethoxystyryl)-DMPX (K-i A(2A) = 15 nM, 167-fold selective). These and other novel compounds are superior to the standard A(2A) adenosine receptor antagonists KF17837 (4) and CSC (5) with respect to A(2A) affinity and/or selectivity.

  DOI：

  10.1021/jm970515+